*2.2.1.4 Nitric oxide (NO) deficiency*

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

*2.1.7 Antidiabetic treatment and macular edema*

retinal-vascular barrier [43–46].

• small vessel wall damage:

• alterations in platelet function

• changes in blood flow

*2.2.1 Lesions in small vessel wall*

by different mechanisms, such as:

tory clinical results.

*2.2.1.1 Aldose-reductase and intracellular polyol pathway*

*2.2.1.2 Advanced glycosylated end products (AGEs)*

microaneurysm formation in retinal capillaries [50].

*2.2.1.3 Oxidative stress and ROS*

**2.2 Pathophysiology**

main factors:

The correlations between antidiabetic mellitus medication and the risk of macular edema is still a subject of research. In a comprehensive systematic review and meta-analyses, Zhu and col. found that insulin use, as well as thiazolinedione (TZD) and meglitinide might increase the risk of macular edema, metformin has no statistically significant effect, while the use of sulfonylureas seems to have a protective role [43]. The physiopathological mechanisms are not completely understood, but experimental studies indicate that insulin and TZD may induce changes in retinal flow and increased expression of VEGF and breakdown of

The pathological changes that lead to diabetic retinopathy are attributable to 3

Microvascular changes in the retinal capillaries are due to chronic hyperglycemia

Aldose reductase is an enzyme that converts glucose to sorbitol, which induces osmotic stress by intracellular accumulation. In animal models, this phenomenon leads to microaneurysmal dilatations of the vascular wall, basal membrane thickening and loss of the pericytes [47]. However, experimental studies of treatment with aldose reductase inhibitors have not obtained satisfac-

Chronic hyperglycemia leads to non-enzymatic glycation or glycoxidation of proteins, resulting in accumulation of AGEs. This process affects both intra- and extracellular proteins, resulting in functional impairment. Deposits of AGEs in the extracellular matrix and subendothelial space lead to permanent alterations of intercellular junctions, monocyte migration and activation of nuclear factor (NF) *κ*B along with activation of pro-inflammatory pathways [48, 49]. In experimental models, increased AGEs accumulation is associated with loss of pericytes and

Hyperglycemia induces mitochondrial dysfunction and endoplasmic reticulum stress, with increased production of free radicals and reactive oxygen species (ROS) accumulation [49]. These degrade lipids, proteins and ribonucleic acid (RNA) chains.

**252**

Hyperglycemia induces decreased synthesis and increased consumption of NO by multiple pathways: activation of protein kinase C (PKC) in endothelial cells, oxidation of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) via aldose reductase pathway, and non-enzymatic production of superoxide by AGEs. NO plays key roles in microcirculation, by regulation of arteriolar tone, platelet stabilization and preventing leukocyte adherence at the vascular wall. Decreased local levels of NO promotes vasoconstriction, microvascular occlusions and secondary retinal ischemia.
